6/29/2015

1

Sarah A. Morrow M.D., M.S., FRCPCAssistant Professor of Neurology

Western UniversityLondon, ON CANADA

Dr. Morrow has no disclosures relevant to this presentation.

6/29/2015

2

Treatment of relapses

Cognitive relapses

Switching therapy Relapse activity MRI activity Clinical worsening (Progression)

Standard of Care: High dose corticosteroids

Postulated to reduce blood brain barrier abnormalities by decreasing peripheral CD4 lymphocytes, pro-inflammatory cytokines, and inhibit class II receptor on endothelial cells

The details….no standard at all

6/29/2015

3

Optic Neuritis Treatment Trial (ONTT)- 250mg IV methylprednisolone (IVMP) q6h for 3 days

- 1 mg/kg/day oral prednisone (OP) for 14 days- Oral placebo

F/U for 2 and 3 yearsResults: IVMP recovered vision faster than placebo

no difference at 6 months

Oral prednisone no better than placebo Higher rate of recurrence in oral group in first two years, but

no longer significant after 3 years

Beck et al NEJM 1992, 1993, Arch Neurol 1995

Not a true comparison of oral and IV treatments - Doses different

- IV 1000mg (divided q6h) vs. oral 1mg/kg OD

- Dosing schedules different - (IV 3 days vs. oral 14 days)

- Only optic neuritis included

6/29/2015

4

Morrow et al Neurology 2004 Randomized, single blind pharmacokinetic study of IV

1000mg methylprednisolone vs. 1250mg oral prednisone

No difference found on AUC analysis

Martenelli et al Neurology 2009 Single blind MRI study No difference in reduction of gad-enhancing lesions or

T2 lesions

Oral versus Intravenous High Doses of Methylprednisolone in Multiple Sclerosis Relapses, a Double Blinded Randomised Controlled Trial

6/29/2015

5

OBJECTIVE: To compare oral versus Intravenous (IV) efficacy and safety of MP 1g/day for 3 days for the treatment of MS relapses.

DESIGN/METHODS:Non- inferiority trial French multicenter, double blinded randomized, non

inferiority, controlled trial. 200 relapsing MS patients Randomized to receive MP 1g/day for 3 days orally or IV. EDSS scores were measured at 3, 8, 28 and 180 days Tolerance was evaluated at 2, 3, 4, 8 and 28 days and safety

data were collected up to 180 days. Primary end-point was the percentage of patients improved

at day 28 (decrease by at least 1 point of the most affected functional system)

No significant difference between oral and IV Improved at 28 days after treatment (77.7% IV, 77.9% oral) 16% of patients on IV methylprednisolone needed retreatment

versus 12.6% on oral treatment 43% on IV treatment totally recovered vs 39% on oral treatment 27.6% of IV treatment had another relapse after a median time

of 86 days, vs. 32% of oral treatment after a median of 90.5 days

Similar adverse event profiles Metallic tastes Hot flashes Headache Insomnia and agitation -- slightly more frequent in the oral

treatment group.

6/29/2015

6

Most Common Reddening of the face Transient ankle edema Elevated mood Insomnia Gastrointestinal

Only in those w/ history of GI issues (Metz 1999)

Rare but worrisome Psychosis Acute pancreatitis Anaphylaxis Transient

hyperglycemia Transient hypertension

Bone demineralization Only seen with multiple

pulses per year

Metz et al Neurology 1999Sellebjerg and the EFNS guidelines Eur J Neurol 2005Leary et al Postgrad J Med 2005

Objective: To determine the frequency and potential predictors of (hypo)manic and depressive symptoms with HDC treatment for MS relapses.

Methods: Consecutive subjects with a relapse)requiring HDC treatment identified. Assessment of before, 3 days post HDC and one month later with:

Mood Disorders Questionnaire (MDQ) for hypomania Beck Depression Inventory - Fast Screen (BDIFS) for depressive symptoms

Results: Eighty eight subjects completed the study. At relapse diagnosis, mean BDIFS score was 4.2 (SD 3.1); mean number of

(hypo)manic symptoms on the MDQ was 4.3 (SD 3.5). Three days after completing HDC treatment, 22.5% had an increase on the

BDIFS and 38.2% endorsed more symptoms on the MDQ. A history of depression (p=0.006) and low reported quality of life (p=0.029)

predicted an increase on the MDQ; Odds of an increase in (hypo)manic symptoms on HDC was 5.6 times higher with

a history of any psychiatric disease/substance abuse (p=0.005). No factor was found to predict worsening on the BDIFS with HDC treatment.

6/29/2015

7

Past steroid use? Ask about any

symptoms with last treatment

Treat symptoms accordingly

1ST treatment? Hx of insomnia? Hx of GERD?

Can prophylactically give perscriptions to be filled as needed

Hx of diabetes?Check BG 4x/day and

adjust medications accordingly

Studies in the past have shown that stopping high doses of corticosteroids after short term use is safe

Perumal et al Eur Neurol 2008 Randomized 285 relapses to taper or placebo post

relapse treatment No difference between two groups on rate of recovery at 3, 6 and 12 months rebound or relapse recurrence

Levic et al J Endo Invest 1996Chrousos et al JAMA 1993

6/29/2015

8

Brainstem relapses and relapses with persistent gad-enhancement often “rebound” after high dose steroids pulse May need steroid taper 60mg X 5 days, followed by 10mg taper q3 days

Has patient had rebound in the past? If so, give a perscription for taper, to be used if rebounds

occurs

What about the first treatment with steroids? Have patient inform you if he/she rebounds after the

high dose

1250mg oral prednisone OR 1000mg IV methylprednisolone Depends on setting, convenience for patient, and relapse

factors

3 to 5 days of treatment

Taper usually not needed

Manage adverse events individually

6/29/2015

9

Corticotropin (as opposed to corticosteroid) Stimulates the adrenal cortex to secrete

Cortisol Corticosterone Aldosterone

Approved in 1978 by FDA to treat MS relapses Not used for several years due to limited

manufacturing AEs similar to corticosteroids

Hoogstraten et al 1990 1 year f/up of 29 MS patients treated with ACTH (IM) vs. placebo ACTH group did better at 1st assessment, but by 6 and 12 months, there

were no longer any significant differences ACTH group had higher risk of relapse in year

Barnes et al 1985 14 MS relapses treated with IVMP 1g daily for 7 days vs. IM ACTH (80U,

60U, 40U, 20U daily each for one week) More rapid improvement at 3 and 28 days with IV MP, but no difference

at 3 months

Thompson et al 1989 61 MS relapses Randomized to IV MP 1X daily for 3 days vs. ACTH (80U for 7 days, 40U

for 4 days, 20 U for 3 days) No difference in rate of recovery or final outcome at 12 weeks

6/29/2015

10

Considered second line therapy after IVMP or dexamethasone, if Cannot tolerate AEs of high dose corticosteroids Have not responded to corticosteroids in past Have difficulty with IV medications because of poor

venous access

IM 80-120U daily for 2-3 weeksOR IM 80U daily for a week followed by a taper

over a week

6/29/2015

11

21

Descriptive Statistics

Status Caseor Control

Mean(SD) N

SDMT_2SDMT at Month –2; value 2nd prior to relapse

D1

.00 control

52.45 (11.305)

115

1.00 case 52.30 (11.645)

53

SDMT_1SDMT at Month –1; value 1st priorto relapse

D1

.00 control

53.39 (11.644)

115

1.00 case 53.64 (10.911)

53

SDMT_1SDMT at Month 1;value 1st after relapse

D1

.00 control

54.70 (11.689)

115

1.00 case 52.40 (11.093)

53

SDMT_2SDMT at Month 2; value 2nd after relapse

D1

.00 control

55.83 (11.972)

115

1.00 case 54.85 (11.122)

53

SDMT_3SDMT at Month 3

D1

.00 control

56.08 (12.205)

115

1.00 case 55.28 (10.994)

53

Between group main effect: P=0.67.Within group main effect: P≤0.01.Interaction: P=0.03.

Control=MS patients without relapses in STRATA; cases=MS patients with relapses in STRATA; D1=dimension 1.

52

53

54

55

56

57

SD

MT

Mea

n S

core

Matched controls without relapsesCases with relapses

Pre 2 Pre 1 Post 1 Post 2 Post 3

22

Descriptive Statistics

Status Caseor Control

Mean (SD) N

MSNQ_2MSNQ at Month –2

D1

.00 control

13.30 (10.959)

115

1.00 case 14.08 (10.612)

53

MSNQ_1MSNQ at Month –1

D1

.00 control

12.95 (10.805)

115

1.00 case 15.04 (11.153)

53

MSNQ_1MSNQ at Month 1

D1

.00 control

12.43 (9.974)

115

1.00 case 15.64 (12.010)

53

MSNQ_2MSNQ at Month 2

D1

.00 control

11.83 (10.010)

115

1.00 case 14.13 (10.925)

53

MSNQ_3MSNQ at Month 3

D1

.00 control

11.86 (10.255)

115

1.00 case 13.85 (11.661)

53

Between group main effect: P=0.22.Within group main effect: P=0.01.Interaction: P=0.09.

11

12

13

14

15

16

MS

NQ

Mea

n S

core

Control=MS patients without relapses in STRATA; cases=MS patients with relapses in STRATA; D1=dimension 1.

Pre 2 Pre 1 Post 1 Post 2 Post 3Matched controls without relapsesCases with relapses

Relapses and cognitive impairment: MSNQMorrow SA et al. J Neurol. 2011

6/29/2015

12

6/29/2015

13

Conclusions

Changes in cognitive function occur during MS relapses

SDMT can be used to detect these changes

25Morrow SA et al. J Neurol. 2011 258(9):1603-8.

6/29/2015

14

Disability

Relapses

Diffuse damage accumulation(neurodegeneration / failure of repair; disability / atrophy)

MRI activity

Focal Inflammation(relapses / MRI lesions)

27

Disease progression2 NEDA-3 defined as:Disease worsening2

No confirmed EDSSprogression3,4

No confirmed relapses3,4

(inflammatory disease activity)

No MRI activity (new / enlarging T2lesions)3,4

NEDA-3, 3-component no evidence of disease activity.Adapted from Barten LJ, et al. Drug Des Devel Ther. 2010;4:343-61. Bevan CJ and Cree BA. JAMA Neurol. 2014; 2. Lublin FD et al. Neurology. 2014; 3. Havrdova E et al. Lancet Neurol. 2009; 4. Giovannoni G et al. Lancet Neurol. 2011.

28

Treatment Optimization in MS:Canadian MS Working Group Updated Recommendations*

Mark S. Freedman1, Daniel Selchen2, Douglas L. Arnold4, Alexandre Prat5, Brenda Banwell3, Michael Yeung6, David Morgenthau2, Yves Lapierre4, on behalf of the Canadian Multiple Sclerosis Working Group

1Ottawa Hospital Research Institute, University of Ottawa, Ottawa2St. Michael's Hospital, Toronto3The Hospital for Sick Children, Toronto, Ontario4Montreal Neurological Institute and Hospital5Centre hospitalier de l'Université de Montréal, Montreal, Quebec6Foothills Medical Centre, Calgary, Alberta, Canada

* Freedman et al. Can J Neurol Sci 2013;40:307-323

6/29/2015

15

558 MS patients – 483 (87%) IFN, 75 (13%) GA Compared non-switchers

1) switchers for ongoing disease activity vs 2) switchers for other reasons

6/29/2015

16

CARRA EUR NEUROL 2008 CASTILLO PLOS ONE 2011

- For inadequate efficacy, the second treatment had a lower ARR (the smallest change was from IFN to IFN) - For AEs, little change in ARRbut this was low before and after (ARR 1.1 pre-switch)

Without switching, MS ptswith high ARR on DMTs will continue to have ongoing relapses

32

Relapse criteria

Level of concern*

Low Medium High

Rate1 relapse in second year of treatment

1 relapse in first year of treatment

>1 relapse in first year of treatment

Severity

Mild Moderate Severe

• Steroids not required • Steroids required• Steroids/hospitalization

required

• Minimal effect on ADL • Moderate effect on ADL • Severe effect on ADL

• 1 FS affected • >1 FS affected • >1 FS affected

• No/mild motor or cerebellar

• Moderate motor/cerebellar involvement

• Severe motor/cerebellar involvement

Recovery • Prompt recovery

• Incomplete recovery at 3 mo.

• Incomplete recovery at 6 mo.

• No functional deficit • Some functional impairment • Functional impairment

* Level of concern determined by meeting at least 1 criterionADL=activities of daily living; FS=functional systems

6/29/2015

17

50 subjects in cladribine RCT with monthly MRIs Gadolinium injected 10 minutes before imaging Used presence of new lesions to predict new clinical

activity (relapse)

6/29/2015

18

Using ≥ 2 relapses as the baseline for comparison (known to increase risk of progression)

• ≥ 2 new GdE lesions were 2x more predictive of EDSS progression

• ≥ 3 new T2 lesions were 3x more predictive

1.05

2.05

3.41

0

1

2

3

4

≥2 relapses ≥2 new GdE lesions

≥3 T2 new lesions

Relative Ability to Predict EDSS Progression

6

MRI activity after 1 year predicts an increase in disability increase in the first 2 years of therapy

7

Active lesions at 1 year Odds ratio 95 % CI p value

≤2 1.0 -<0.0001

>2 8.3 3.1 to 21.9

Prospective, longitudinal study of RRMS treated with IFN-β. N=152 patients followed for ≥2 years

Evaluation of predictive value of MRI after 1 year of treatment

6/29/2015

19

37

MRI criteria Level of concern*

Activity on MRI* Low Medium High

New Gd-enhancing lesions ORAccumulation of new T2 lesions per year

1 lesion 2 lesions ≥3 lesions

* Gd-enhancing lesions more reliable than new T2 lesions. New T2 lesion counts require high-quality comparable MRI scans and interpretation by qualified individuals.

• Routine follow-up MRI with gadolinium is recommended 12 months after treatment initiation

6/29/2015

20

Predictor of progression(1 year after starting therapy)

Proportion of the Treatment Effect on Disability

Progression

Active T2 lesions 63%

Clinical relapses 61%

New and enlarging T2 lesions + clinical relapses 100%

MRI, magnetic resonance imaging.*Faculty expert opinion.Adapted from Sormani MP, et al. Neurology. 2011;77(18):1684-90.

8

Caveat: These are short-term data; lesions and relapses predict disability over 2 years only. There remains a need to integrate brain atrophy for more

meaningful, longer-term assessment.*

40

Progression criteria Level of concern*

EDSS score Low Medium High

≤ 3.5 ≤1 point 2 points at 6 mo.*>2 points at 6 mo.*2 points at 12 mo.*

4.0 to 5.0 <1 point 1 point at 6 mo.*>1 points at 6 mo.*1 point at 12 mo.*

≥ 5.5 - - 0.5 points at 6 mo.* >0.5 points at 6 mo.*

Clinically documented progression

No motorSome motor, cerebellar or cognitive

Pronounced motor, cerebellar or cognitive

Minor sensoryMultiple EDSS domains affected

Multiple EDSS domains affected

T25FW**≤20% confirmed at 6 mo.

>20% and <100% increase confirmed at 6 mo.

≥100% increase confirmed at 6 mo.

* If EDSS progression alone is used to assess treatment response, any change requires subsequent confirmation at 3-6 months. ** Timed 25-foot walk tested at baseline; with aid, if required

6/29/2015

21

Prompt treatment with high dose corticosteroids will lead to improvement of relapse symptoms Equivalent high doses of

IV or oral appropriate Can use ACTH if poor

tolerance corticosteroids

Cognitive relapses can occur and respond to treatment similar to “physical symptom” relapses

MRI activity and progression are also indicators of poor response to treatment

Consider switching treatment if: More than one mild

relapse One moderate to severe

relapse Evidence of multiple new

T2 or gad lesions on MRI Significant short term

progression due to underlying inflammation